BRPI0809220A2 - METHOD FOR THE PRODUCTION OF QUINOLONA CARBOXYLIC ACID DERIVATIVE - Google Patents

Abstract

The present invention relates to a method for producing a quinolone compound having high antibacterial activity and high safety, at high yield and in a simple manner. A quinolonecarboxylic acid derivative (1) of interest is produced through a one-pot manner by reacting a compound (2) with a salt of a cyclic amine (3) and with a boron derivative in a solvent in the presence of a base.

Description

“METHOD FOR THE PRODUCTION OF QUINOLONA CARBOXYLIC ACID DERIVATIVE”

Field of the Invention

The present invention relates to a method for producing a quinolone compound having high antibacterial activity and high safety in high yield and in a simple manner.

Background Technique

Generally, a quinolone compound has a cyclic amine substituent including a second amino moiety at position 7 (or an equivalent position) of the quinolone sketch. Such quinolone compounds are generally synthesized by reaction of a cyclic amine compound with a 7-halogenated quinolonecarboxylic acid compound. In order to enhance the specificity of the reaction and production site, the carboxylic acid moiety of a quinolonecarboxylic acid compound is transformed into a borofluoric acid ester moiety or a boric acid ester moiety, followed by reaction with a carboxylic acid moiety. cyclic amine (see Patent Documents 1-3 and Non-Patent Documents 1-4).

In addition, from an industrial point of view, there have been methods developed for the production of highly efficient quinolonecarboxylic acid derivatives; for example, a production method wherein an alkyl borate is employed as an additive (Patent Document 4), and a pot method (Patent Document 5).

Patent Document 1: JP-A-1987-252772

Patent Document 2: JP-A-1988-316757

Patent Document 3: JP-A-1991-95177

Patent Document 4: JP-A-1993-294938

Patent Document 5: WO 2005/047260

Non-Patent Document 1: Majid M. Heravi et al., Journal of Chemical Research, 2005, 579.

Non-Patent Document 2: Liu Ming-Liang et al., Chinese Journal of New Drugs, 2004, 13, 12, 1130.

Non-Patent Document 3: Liu Ming-Liang et al., Chinese Journal of Pharmaceuticals, 2004, 35, 3, 129.

Non-Patent Document 4: Liu Ming-Liang et al., Chinese Journal of Pharmaceuticals, 2004, 35, 7, 385.

Description of the Invention

Problems to be solved by the Invention

When the method described in Patent Document 3 is employed, a freeform amine compound is reacted to produce the quinolonecarboxylic acid derivatives in high yield (72 to 81%). However, free-form cyclic amine compounds have less chemical stability and poor handling which are problematic. And then, when a salt-shaped cyclic amine compound, which is excellent in stability and handling, is employed in a reaction, the production of the quinolonecarboxylic acid derivative (49%) does not achieve the production which is obtained by employing a free-form amine compound. Thus, the use of such an amine compound salt is also still problematic in terms of industrial production.

In the method described in Patent Document 4, the non-quinolonecarboxylic acid derivative 10 can be produced at the same time as when a cyclic amine salt compound having high stability and high maneuverability is employed. In addition, the method described in Patent Document 4 includes a step of transforming a carboxylic acid moiety to a borofluoric acid ester by the use of an expensive silylating agent (i.e. through the silyl ester), preparing this nuisance method. For this reason, there is demand for a production method which can be carried out in a simple manner.

Thus, an object of the present invention is to establish a novel process which is beneficial for the global environment, the process employing a high stability, high handling cyclic amine salt compound which carries out the reaction with high efficiency; preventing the use of an expensive silylating agent; and reducing process waste.

Problem Solving Means

The present inventors have performed extensive studies on the above process, and have found that upon admission of the compound represented by formula (2), a cyclic amine salt, and a boron derivative to react in a solvent in the presence of a Based on this, the quinolonecarboxylic acid derivatives can be efficiently synthesized in a pot reaction without forming a silyl ester, thereby performing an industrially advantageous method for producing a quinolone-based synthetic antibacterial agent. The present invention has been made based on this finding.

The present invention is directed to a method for producing a compound represented by formula (1): wherein:

R1 represents an optionally substituted C1 to C6 alkyl group, an optionally substituted C3 to C6 cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group;

R2 represents an optionally substituted amino group, an atom of

hydrogen, a hydroxyl group, a thiol group, a halogenomethyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or a C1 to C6 alkoxy group;

R3 and R4 each independently represent a C3 to C6 cycloalkyl group, a hydrogen atom, a halogen atom, a phenyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a C2 group C6 to alkenyl, or a C2 to C6 alkynyl group, wherein the cycloalkyl group may have an amino group as a substituent; each of the alkyl group, alkoxy group, alkenyl group, and alkynyl group may be straight or branched; and the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a C1 to C6 alkylthio group, a C1 to C6 alkoxy group, a C3 group to C6 cycloalkyl, a C1 to C6 alkylamino group, a C3 to C6 cycloalkylamino group, a C1 to C6 alkoxy group, a phenyl group which may be substituted by a C1 to C6 alkoxy or halogen atom group , a furyl group which may be substituted by a C1 to C6 alkoxy or halogen atom group, and a thiazolyl group which may be substituted by a C1 to C6 alkoxy or halogen atom group, or R3 and R4 can be linked together to form

(a) spiro ring structure of a 3 to 6 membered ring structure including the carbon atom to which R 3 and R 4 are attached, wherein the spiro ring may have a nitrogen atom, an oxygen atom, or a sulfur atom, such as a ring member atom; the ring formed may be substituted by a halogen atom, a C1 to C6 alkyl group, or an amino group; and the alkyl group may have a group selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group as a substituent, or (b) exo-methylene group bonded through of a double bond, wherein the exomethylene group may have one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a C1 to C6 alkylthio group, and a C1 to C6 group alkoxy;

"A" represents a nitrogen atom or a partial structure represented by the

following formula:

(wherein X2 represents a hydrogen atom, a hydroxyl group, a cyano group, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogenomethyl group, or a group of halogenomethoxy wherein X2 and R1 mentioned above may be integrated with a portion of the sketch to form a ring, and the ring formed may be a C1 to C6 alkyl group as a substituent);

W represents -CHR5 -, -O-, or -NR6 - (wherein R5 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a C2 to C6 alkenyl, C2 to C6 alkynyl group, or C1 to C6 alkoxy group, the cycloalkyl group may have an amino group as a substituent, the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a C1 to C6 alkylthio group, and a C1 to C6 alkoxy group; R5 and R3 or R4 mentioned above may together form a C3 to C6 cycloalkane or a 5 to 7 membered heterocycle saturated with a carbon atom to which these R s are attached, and the formed cycloalkane or saturated heterocycle may have a C1 to C6 alkyl group or an amino group as a substituent, and R 6 represents an atom hydrogen, a C1 to C6 alkyl group, or a C3 to C6 cycloalkyl group);

X1 represents a hydrogen atom or a halogen atom;

Y represents a hydrogen atom, or an amino group, a C1 to C6 alkyl group, a C1 to C6 alkylamino group, a C3 to C6 cycloalkyl group, or a group which can be easily transformed by chemical means by an amino group or a C 1-6 alkylamino group, these groups each being attached to any saturated heterocyclic ring carbon atom; and

n is 0 to 2, a salt thereof, or a hydrate of the compound or salt, characterized in that the method comprises

admit to cause a reaction in a mixture containing a compound represented by the formula (2): (where X represents a halogen atom, and R11 R2, X11 and A have the same meanings as defined above), a salt of a compound represented by formula (3):

(wherein W, Y, R31 R41 and n have the same meanings as defined above), and one

boron derivative in a solvent in the presence of a base, thereby to form a boron chelate compound, and

remove a portion of boron chelate from the boron chelate compound.

Effects of the Invention

In accordance with the present invention, a quinolonecarboxylic acid derivative is

It is converted to a borofluoric acid ester or boric acid ester thereof, which has enhanced reactivity for the production of a quinolone derivative, and the formed boron-containing derivative is employed as a starting material for the condensation reaction. Therefore, the boron-containing derivative is condensed with a cyclic amine salt compound having high stability and maneuverability in the presence of a base in a reaction mixture. This process can be performed simply without isolating the boron containing derivative, thereby reducing the loss of insulation. Since the condensation reaction can be carried out in a one-pot manner, the possible exposure of workers to harmful intermediates can be reduced, and the yield of production can be remarkably enhanced. Hence, from an industrial point of view, a target compound represented by formula (1) can be produced in high production in a simple manner.

Best Ways to Perform the Invention

The quinolonecarboxylic acid compound employed in the present invention is represented by formula (2): wherein:

R1 represents an optionally substituted C1 to C6 alkyl group, an optionally substituted C3 to C6 cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted heteroaryl group;

R2 represents an optionally substituted amino group, a hydrogen atom, a thiol group, a halogenomethyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or a C1 -C6 alkoxy group;

X represents a halogen atom;

X1 represents a hydrogen atom or a halogen atom; and

"A" represents a nitrogen atom or a partial structure represented by the following formula:

(where X 2 represents a hydrogen atom, a hydroxyl group, a

cyano, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogenomethyl group, or a halogenomethoxy group, wherein X2 and R1 may be integrated with a sketch moiety to form a ring, and the ring formed may have a C1 to C6 alkyl group as a substituent). Hereinafter, the compound is referred to as compound (2).

When R1 is an optionally substituted alkyl C1 to C6 group, the examples

of the substituent include a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group. Of these, a halogen atom is preferred.

When R1 is a C1 to C6 alkyl group, the alkyl group may be straight or branched. Specific examples include methyl, ethyl, isopropyl, sec-butyl, and tert-butyl.

Of these, ethyl and tert-butyl are preferred.

When R1 is a halogen substituted C1 to C6 alkyl group, the alkyl moiety may be straight or branched. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Of these, ethyl and tert-butyl are preferred. The halogen atom which serves as an alkyl group substituent is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. Examples of such halogen substituted alkyl groups include fluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1-dimethyl-2-fluoroethyl, 1-methyl5 1- (fluoromethyl) - 2-fluoroethyl, and 1,1- (difluoromethyl) -2-fluoroethyl. Of these, 2-fluoroethyl and 1,1-dimethyl-2-fluoroethyl are preferred.

When R1 is an optionally substituted C3 to C6 cycloalkyl group, example of the cycloalkyl group includes cyclopropyl, cyclobutyl, and cyclopentyl. Of these, cyclopropyl is preferred. The cycloalkyl group substituent is preferably a halogen atom, a methyl group, or a phenyl group, more preferably a halogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom, with a fluorine atom being particularly preferred. The substituent number on the cycloalkyl group may be 1 or 2, but is preferably 1. In other words, a monofluorocyclopropyl group is preferred, with a 1,2-cis-2-fluorocyclopropyl being more preferred, a group of ( 1R, 2S) -2-fluorocyclopropyl being particularly preferred.

When R1 is an optionally substituted phenyl group, examples of the substituent include a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group. Of these, a halogen atom is preferred.

When R1 is a halogen substituted phenyl group, the halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. The substituted halogen atom number in the phenyl group is preferably 1 or

2. The halogen substituted phenyl group may additionally have a substituent. The substituent is preferably amino, hydroxyl, or methyl. Examples of such optionally substituted halogen substituted phenyl groups include a group of 2-25 fluorophenyl, a group of 4-fluorophenyl, a group of 2,4-difluorophenyl, and a group of 5-amino-2,4-difluorophenyl . Of these, a 2,4-difluorophenyl group and a 5-amino-2,4-difluorophenyl group are preferred.

When R1 is an optionally substituted heteroaryl group, the heteroaryl group may be a 5-membered or 6-membered aromatic heterocyclic group having 30 one or more heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. . Among such a heteroaryl group, a 5- or 6-membered nitrogen-containing aromatic heterocyclic group having 1 or 2 nitrogen atoms is preferred. Specific examples include pyridyl, pyrimidyl, pyridazinyl, imidazolyl, thiazolyl, and oxazolyl. Of these, pyridyl is preferred.

When R1 is an optionally substituted heteroaryl group, examples of the

substituents include a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group. Of these, a halogen atom is preferred. The halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. The substituted halogen atom number in the heteroaryl group is 1 or 2. Preferred examples, moreover, include an amino group and a hydroxyl group as well as a methyl group.

The halogen substituted heteroaryl group may furthermore have a

substituent. Such an optionally substituted halogen substituted heteroaryl group is preferably a 6-amino-3,5-difluoropyridin-2-yl group.

The above-mentioned R1 is preferably a cyclopropyl group or a 1,2-cis-2-fluorocyclopropyl group, more preferably a (1R, 2S) -2-fluorocyclopropyl group. R2 represents a hydrogen atom, an amino group, a hydroxyl group,

a thiol group, a halomethyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or a C1 to C6 alkoxy group.

When R2 is an amino group, the amino group may have one or two groups selected from the group consisting of a formyl group, a C1 to C6 alkyl group, and an acyl C2 to C5 group as substituents.

When R2 is a C1 to C6 alkyl group, the alkyl group may be straight or branched and is preferably methyl, ethyl, propyl, or isopropyl, with methyl being particularly preferred.

When R2 is a halogenomethyl group, the halogen atom is preferably a fluorine atom, and the number of halogen atoms may be 1 to 3.

When R2 is an amino group, a hydroxyl group, or a thiol group, these groups may be protected by a generally employed protecting group.

Examples of such protecting groups include (substituted) alkoxycarbonyl groups such as tert-butoxycarbonyl and 2,2,2-trichloroethoxycarbonyl; (substituted) 25 aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, and pnitrobenzyloxycarbonyl; (substituted) acyl groups such as acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, and benzoyl; (substituted) alkyl groups and (substituted) aralkyl groups such as tert-butyl, benzyl, p-nitrobenzyl, pmethoxybenzyl, and triphenylmethyl; (substituted) esters such as methoxymethyl, tert-butoxymethyl, tetrahydropylyl, and 2,2,2-trichloroethoxymethyl; and (substituted alkyl and / or aralkyl) silyl groups such as trimethylsilyl, isopropyldimethylsilyl, and tert-butyldiphenylsilyl. Compounds protected with such a substituent are particularly preferred as intermediates for the production of quinolone carboxylic acid derivatives.

Examples of the C1 to C6 alkoxy group include methoxy, ethoxy, propoxy, and butoxy. Of these, methoxy is preferred.

The C 2 to C 6 alkenyl group or the C 2 to C 6 alkynyl group preferably have two carbon atoms. Among the above-mentioned R2S, a hydrogen atom, an amino group, a hydroxyl group, a methyl group, and a methoxy group are preferred, with a hydrogen atom and an amino group being particularly preferred.

X represents a halogen atom, and X1 represents a hydrogen atom or a halogen atom. Examples of such halogen atoms include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. X1 is preferably a hydrogen atom or a fluorine atom.

"A" represents a nitrogen atom or a partial structure represented by formula (II):

(X2 represents a hydrogen atom, a hydroxyl group, a cyano group, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogenomethyl group, or a halogenomethoxy group) .

When A is a partial structure represented by formula (II) and X 2 is a C1 to C6 alkyl group, the alkyl group may be straight or branched, and is preferably methyl, ethyl, propyl, or isopropyl. Of these, methyl and ethyl are more preferred, with methyl being even more preferred. The C1 to C6 alkoxy group may be an alkoxy group derived from the above alkyl group. Among such groups, a C1 to C3 alkyl group and a C1 to C3 alkoxy group are preferred, with methyl and methoxy being particularly preferred.

The halogen atom is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. The halogen atom of the halomethyl group is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. Examples of the halomethyl group include fluoromethyl, difluoromethyl, and trifluoromethyl. Similarly, the halogen atom of the halogenomethoxy group is preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom. Examples of the halomethoxy group include fluoromethoxy, difluoromethoxy, and trifluoromethoxy.

When A is a partial structure represented by formula (II), X 2 and R 1 may form a cyclic structure together with a sketch portion of the quinolone (3-atom structure: that is, the carbon atom to which X 2 is attached; nitrogen atom to which R1 is attached, and the carbon atom to which both of the carbon atom former and the last nitrogen atom are attached). The ring thus formed is preferably a 5 to 7 membered ring and may be saturated or unsaturated. The cyclic structure may have an oxygen atom, a nitrogen atom, or a sulfur atom as a ring member atom and may be further substituted by a C1 to C6 alkyl group as mentioned with respect to X2. Preferably, the cyclic structure has an oxygen atom and is preferably substituted by a methyl group. An example of such preferred structures is -O-CH 2 -CH (-CH 3) -, in which the right-sided carbon atom is attached to a nitrogen atom.

When A is a partial structure represented by formula (II) and the substituent X2 does not form a cyclic structure, X2 is preferably methyl, ethyl, methoxy, difluoromethoxy, cyano, a fluorine atom, or a chlorine atom, particularly preferably methyl, methoxy, or difluoromethoxy.

Where A is a partial structure represented by formula (II) and the substituent X 2 forms a cyclic structure, the cyclic structure is preferably a 2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1, 2,3-de] [1,4] benzoxazine-6-carboxylic acid. Among such sketches, 3- (S) -methylpyridobenzoxazine sketch is particularly preferred.

In accordance with the method of the present invention, a cyclic amino substituent

having an amino moiety is introduced at position 7 or an equivalent site of the quinolon compound of compound (3). Examples of such substituents include (7S) -7-amino-7-methylpiro [2.4] ept-5-yl, 3-methylaminopiperidin-1-yl, 4-methylpiperazin-1-yl, and the following substituents.

Me ^

HN N - Me-N N - Et-N N - HN N - HN N - HN N -

Me Et Me

Me-N N-HN N-HN N-HN N-HN N

y w ■ y ■ y ‘'

t>. o- ■ c- · / t>.

u ^ Cn: <t> - cp ”

c “x>

2 \ y- ■ '^ -' ^> -, "'^ 0 · - ·.

N- N

Ph

H, N

20

N- H2N 'γ-Λ H2N ^ Va H * N', N

Among them, preferred are the following groups. Me

Therefore, compound (3), which is a cyclic amine compound capable of providing these substituents, is preferably employed in the method of the present invention.

No particular limitation is imposed on the salt of compound (3), as the salt is pharmaceutically acceptable. Examples of the salt include mineral acid salts such as hydrochlorides, hydrobromides, hydroiodides, phosphates, nitrates, and sulfates; benzoates; organic sulfonic acid salts such as methanesulfonates, 2-hydroxyethanesulfonates, and ptoluenesulfonates; and organic carboxylic salts such as acetates, propionates, oxalates, malonates, succinates, glutarates, adipates, tartrates, maleates, malates, and mandelates.

The base may be organic or inorganic. Examples of the base which may be employed in the present invention include hydroxides, carbonates, hydrogencarbonates, and alkoxides of an alkali metal or an alkaline earth metal (e.g. sodium, potassium, lithium, magnesium, or calcium); metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; alkyl lithium reagents such as n-butyllithium, methyl lithium, lithium diisopropylamide; tertiary amines such as trimethylamine, triethylamine, tributylamine, and N, Ndiisopropylethylamine; and heterocyclic compounds such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorphorin, pyridine , and Nmethylpyridine. Of these, tertiary amines such as trimethylamine, triethylamine, tributylamine, and α, β-diisopropylethylamine, and heterocyclic compounds such as 1,8-diazabicyclo [5.4.Ojundec7-eno (DBU), 1,8-diazabicyclo [4.3.0] non -5-Ene (DBN), dimethylaniline, N-methylmorphine, pyridine, and N-methylpyridine are preferred, with triethylamine being particularly preferred. The base is generally employed in an amount, relative to the amount of compound (2), 3 to 10 times per mole (ratio per mole), particularly preferably employed in an amount of 4 to 6 times per mole (ratio per mole). No particular limitation is imposed on the solvent employed in the present invention as it does not prevent the reaction. Examples of hydrocarbon solvents include n-hexane, npentane, benzene, toluene, xylene, chlorobenzene, and xylene. Examples of alcohol solvents include methanol, ethanol, propanol, isopropanol (IPA) 1-n-butanol, and t-butanol. Examples of ether solvents include diethyl ether, diisopropyl ether (IPE), methyl butyl ether (MTBE), tetrahydrofuran (THF), cyclopentyl methyl ether, dimethoxyethane, and 1,4-dioxane. Examples of amide solvents include dimethylformamide (DMF), dimethylacetamide (DMAc) 1 and N-methyl-2-pyrrolidone (NMP). Examples of cyclic urea solvents include 1,3-dimethyl-2-imidazolidinone (DMI), and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) 10 pyrimidinone (DMPU). Examples of halocarbon solvents include chloroform, methylene chloride, and 1,2-dichloroethane (EDO). Examples of the solvent, moreover, include dimethyl sulphoxide (DMSO) 1 sulforane, acetonitrile, acetate esters, and acetone. These solvents may be employed separately or in combination of two or more species. Among these solvents, amide solvents include dimethylformamide (DMF), dimethylacetamide (DMAc), and N-methyl-2-pyrrolidone (NMP), and acetonitrile are preferred, with acetonitrile being particularly preferred. The amount of solvent, which cannot be unambiguously predetermined, is generally from about 1 to about 100 times by weight relative to that of compound (2), preferably from about 5 to about 15 times by weight. .

The boron derivative is preferably a trialogenoboro compound plus

preferably a trifluoroboro compound. Trifluoroboro is preferably employed as an ether complex. Examples of such ether complexes include diethyl ether complex and tetrahydrofuran complex. The boron derivative is generally employed in an amount, relative to the amount of compound (2), 1 to 10 times 25 mole (ratio per mole), particularly preferably employed in an amount of 1.5 to 3. times in mole (ratio per mole).

In the method of the present invention, a tertiary amine salt is preferably present in the reaction mixture. Among such salts, tertiary amine acid addition salts are preferably employed. No particular limitation is imposed on the tertiary amine, since the amine is natural tertiary, and any of the aliphatic amines, aromatic amines, saturated or unsaturated heterocyclic amines, and complex amines thereof may be employed. Examples of the tertiary amine include the above-mentioned trialkylamines (e.g. triethylamine, β, β-diethylisopropylamine, and tributylamine); dialkylarylamines (e.g., dimethylaniline and diethylaniline); N-methylmorphorin; and N-methylpiperidine. The acid which forms the acid-addition salts may be an inorganic acid or an organic acid. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid; organic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, and malonic acid; and sulfonic acids such as ptoluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, trifluoromethanesulfonic acid, and camphorsulfonic acid. Among these salts, inorganic salts are preferred, and, for example, hydrochlorides are preferably employed. Generally, the amount of the tertiary amine salt employed with respect to that of compound (2) is preferably about 1 to 10 mole (ratio per mole), particularly preferably 1.5 to 3 mole. (ratio per mole).

The tertiary amine salt is preferably added, particularly when the acid which forms the cyclic amine salt compound to introduce a substituent is a weak acid.

The reaction temperature may be in the range of ambient temperature to solvent boiling point. The reaction completes over a period of about 30 minutes to 78 hours.

By the above procedure, a quinolone carboxylic acid compound in which the carboxylic acid moiety has been transformed to a boron chelate substituent is produced. The boron chelate substituent is removed by hydrolysis upon completion of the reaction with a cyclic amine. When the amino group has been protected, the amino group is unprotected, whereby a quinolone compound of interest can be produced. No particular limitation is imposed under the conditions under which hydrolysis removes a boron substituent is performed, and hydrolysis is generally performed under the conditions employed. For example, hydrolysis may be carried out in a hydrous alcoholic solvent containing methanol, ethanol, etc., or in a hydrated amide solvent containing dimethylformamide (DMF), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), etc. with heating. The reaction is preferably carried out at a temperature between 80 ° C and the boiling point of the solvent employed. Deprotection may be performed under appropriate conditions depending on the protecting group employed. For example, the above hydrolyzate is subjected to hydrogenolysis or treatment with concentrated hydrochloric acid. Upon completion of the reaction, the reaction mixture is made alkaline with, for example, aqueous sodium hydroxide, and neutralized with an appropriate acid such as hydrochloric acid. Precipitated crystals are recovered by filtration or extracted with a solvent such as chloroform. The compound thus produced is purified by, for example, dissolving in a suitable solvent for recrystallization, whereby a quinolone compound of interest may be produced.

Examples

The present invention should be close to that described in detail by means of the following

examples, which should not be construed as limiting the invention either.

Example 1 7-N (7S) -7-Amino-7-Methylpyror-2.41hept-5-yn-1,4-dihydro-6-fluoro-1- (1R.2SV2-fluorocyclopropin-8-methoxy-4-acid) dihydrate oxo-3-auinolinecarboxylic

A solution of acetonitrile (800 mL) containing 6,7-difluoro-1,4-dihydro-1 - [(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 g ), 5-benzyl- (7S) -7-methyl-5-azaspiro [2.4] heptan-7-amine dihydrochloride (90 g), triethylamine (39.9 mL), and boron trifluoride-tetrahydrofuran complex (63.4 mL) were stirred at room temperature for 30 minutes. Boron trifluoride-tetrahydrofuran complex (6.3 mL) was further added to the solution, followed by stirring for one hour at the same temperature. Triethylamine (159.5 mL) was further added to the reaction mixture, followed by stirring at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and methanol (900 mL) was added to the residue. The mixture was refluxed for 6 hours. After cooling to room temperature, the mixture was stirred at 40 ° C for 5 hours under hydrogen in the presence of 5% Pd-C (4.5 g). Subsequently, triethylamine (90 mL) and water (225 mL) were added to the reaction mixture thus obtained, followed by stirring at 40 ° C for one hour. Pd-C was removed by filtration, and the filtered liquid was concentrated under reduced pressure. Water (720 mL) and methanol (180 mL) were added to the residue, and the pH of the product was adjusted to 8 by the use of 5N aqueous sodium hydroxide solution. The mixture thus obtained was stirred at 60 ° C for 40 minutes, and the pH of the product was adjusted to 7 by the use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for one hour. The crystals thus produced were filtered off and dried to thereby yield 120.9 g of the title compound as light brown crystals (yield: 91%).

1H-NMR (400MHz, 0.1 N-NaOD) δ ppm: 0.48-0.56 (2H, m), 0.66-

0.76 (2H, m), 1.12 (3H, s), 1.42-1.63 (2H, m), 3.55 (3H, s), 3.59-3.72 (4H, m), 3.98-4.03 (1H, m), 4.79-5.03 (1H, m), 7.65 (1H, d, J = 13.9 Hz), 8.44 (1 H, s)

Elemental Analysis: Calc. C 5.38% H 5.93% N 9.07%

Obsd. C 55.19% H 5.98% N 9.19%

Example 2

7-r (7S) -7-Amino-7-methyl-Diroyl 2.41hept-5-yl-1-4-dihydro-6-fluoro-1- acid dihydrate

IY1R.2S) -2-fluorocyclopropyl-8-methoxy-4-oxo-3-auolinolinecarboxylic acid

A solution of acetonitrile (24 mL) containing 6,7-difluoro-1,4-dihydro-1 - [(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g ), (7S) -7-methyl-5-azaspiro [2.4] heptan-7-amine dihydrochloride (3 g), triethylamine (1.34 mL), and boron trifluoride35 tetrahydrofuran complex (2.68 g) were stirred at room temperature. room for 30 minutes. Boron trifluoride-tetrahydrofuran complex (0.27 g) was further added to the solution, followed by stirring for one hour at the same temperature. Triethylamine (5.37 mL) was further added to the reaction mixture, followed by stirring at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 2 hours, and the solvent was evaporated. 90% hydrated methanol was added to the residue, and the pH of the product was adjusted to 8 by the use of 5N aqueous sodium hydroxide. The mixture thus obtained was stirred at 60 ° C for 40 minutes, and the product pH was adjusted to 7 by using 5N aqueous sodium hydroxide solution, followed by stirring at 5 ° C for 16 hours. The crystals thus produced were filtered off and dried to thereby yield 4.23 g of the title compound (yield: 93%). The 10 spectral data of this compound coincide with those obtained in Example 1.

Example 3

1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- (3-methylaminopiperidin-1-0-4-oxo-3-quinolinecarboxylic acid dihydrate

A solution of acetonitrile (30 mL) containing 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), 3-methylaminopiperidine dihydrochloride (2.1 g ), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) were stirred at room temperature for 2 hours. Atriethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 6 hours, and the solvent was evaporated under reduced pressure. 80% hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 8 by the use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. The crystals thus produced were filtered off and dried to thereby yield 3.98 g of the title compound (yield: 92%).

1H-NMR (400MHz, DMSO-d6) δ ppm: 0.90-1.31 (4H, m), 1.31-2.12 (4H, m), 2.67-3.71 (5H, m) 3.77 (3H, s), 3.98-4.09 (1H, m), 7.85 (1H, d, J = 11.1 Hz), 8.8 (1H, s)

Elemental Analysis: Calc. C, 56.69%, H, 6.62%, N, 9.74%

Obsd. C, 56.48%, H, 6.63%, N, 9.86%

Example 4

1-Cyclopropyl-1,4-dihydro-6-fluoro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-3-auinolinecarboxylic acid hydrate

A solution of acetonitrile (30 mL) containing 1-cyclopropyl-6,7-difluoro1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), 2-methylpiperazine dihydrochloride (1.93 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) were stirred at room temperature for one hour. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 5 hours, and the solvent was evaporated under reduced pressure. 80% hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, 5 followed by stirring at room temperature for 16 hours. The crystals thus produced were filtered off and dried to thereby yield 3.55 g of the title compound (yield: 91%).

1H-NMR (400MHz, CDCl3) δρριτι: 1.02-1.31 (7H, m), 2.92-3.53 (7H, m), 3.77 (3H, s), 3.91-4 11.11 (1H, m), 7.85 (1H, d, J = 12.3 Hz), 8.79 (1H, s)

Elemental Analysis: Calc. C, 59.37%, H; 6.03%, N; 10.93%

Obsd. C 59.49% H 5.77% N 11.03%

Example 5

9-Fluoro- (3SVmeti-10- (4-methylpiperazin-1-yn-7-oxo-2,3-dihydro-7Hpyridofl-2,3-de1-1,4-benzoxazine-6-carboxylic acid) A solution of acetonitrile (30 mL ) containing 9,10-difluoro- (3S) -methyl-7-acids

oxo-2,3-dihydro-7H-pyrido [1,2l-de] -1,4-benzoxazine-6-carboxylic acid (3 g), 4-methylpiperazine dihydrochloride (2.22 g), triethylamine (1.43 mL), and the boron trifluoride-tetrahydrofuran complex (2.84 g) were stirred at room temperature for 30 minutes. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 24 hours, and the solvent was evaporated under reduced pressure. Ethanol (15 mL) was added to the residue, and the mixture was stirred at room temperature for 16 hours. The crystals thus produced were filtered off and dried, to thereby yield 3.55 g of the title compound (yield: 92%).

1H-NMR (400MHz, CDCl3)? Ppm: 1.63 (3H, d, J = 7Hz), 2.38 (3H, s), 2.54-2.60 (4H, m), 3.40-3 , 44 (4H, m), 4.35-4.52 (3H, m), 7.76 (1H, d, J = 11.8 Hz), 8.64 (1H, s)

Elemental Analysis: Calc. C, 59.82%, H, 5.58%, N, 11.63%

Obsd.C; 60.01%, H, 5.69%, N, 11.53%

Example 6

7-r (3R) -3-H-tert-Butoxycarbonylaminocyclopropin-pyrrolidin-1-yn-1-r (1R.2SV2-fluorocyclopropin-1,4-dihydro-8-methoxy-4-oxo-3-auinolinecarboxylic acid

An acetonitrile solution (45 mL) containing 7-fluoro-1 - [(1R, 2S) -2-fluorocyclopropyl] -8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3 g) triethylamine hydrochloride (2.8 g), and boron trifluoride-tetrahydrofuran complex (2.84 g) were stirred at room temperature for 30 minutes. The tert-Butyl {1 - [(3R) -pyrrolidin-3-yl] cyclopropyl} carbamate oxalic salt (3.54 g) and triethylamine (5.71 mL) were further added to the reaction mixture. followed by stirring for 10 hours at the same temperature. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 12 hours, and the solvent was evaporated under reduced pressure. 80% hydrated methanol (20 mL) was added to the residue, and the product pH was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 60 ° C for 30 minutes and at room temperature for 16 hours The crystals thus produced were filtered off and dried to thereby yield 4.79 g of the title compound (yield: 94%).

1H-NMR (400MHz, CDCl3) δppm: 0.68-0.95 (4H, m), 1.29-1.58 (2H, m), 1.42 (3H, s), 1.71-

1.91 (1H, m), 2.03-2.15 (1H, m), 2.22-2.40 (1H, m), 3.36-3.71 (4H, m), 3.52 (3H, s), 3.79-3.90 (1H, m), 4.74-

5.05 (1H, m), 4.99 (1H, brs), 6.94 (1H, d, J = 9.2Hz), 8.06 (1H, d, J = 9.2Hz) ), 8.65 (1H, d, J = 3.1 Hz), 15.18 (1H, brs)

Elemental Analysis: Calc. C 62.26% H 6.43% N 8.38%

Obsd. C 62.14% H 6.47% N 8.43%

Claims (4)

Method for producing a compound represented by the formula, characterized in that (1): wherein R1 represents an optionally substituted C1 to C6 alkyl group, an optionally substituted cycloalkyl C3 to C6 group, an optionally phenyl group substituted, or an optionally substituted heteroaryl group; R2 represents an optionally substituted amino group, a hydrogen atom, a hydroxyl group, a thiol group, a halogenomethyl group, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 group alkynyl, or a C1 to C6 alkoxy group; each of R3 and R4 independently represents a C3 to C6 cycloalkyl group, a hydrogen atom, a halogen atom, a phenyl group, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a C2 to C6 alkenyl group, or a C2 to C6 alkynyl group, wherein the cycloalkyl group may have an amino group as a substituent; each of the alkyl group, alkoxy group, alkenyl group, and alkynyl group may be straight or branched; and the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a C1 to C6 alkylthio group, a C1 to C6 alkoxy group, a C3 group a C6 to C6 cycloalkyl group, a C1 -C6 alkylamino group, a C3 to C6 cycloalkylamino group, a phenyl group which may be substituted by a C1 to C6 alkoxy group or a halogen atom, a furyl group which may be substituted by a C1 to C6 alkoxy group or a halogen atom, and a thiazolyl group which may be substituted by a C1 to C6 alkoxy group or a halogen atom, or R3 and R4 may be attached each other to form (a) spiro ring structure of a 3- to 6-membered ring structure including the carbon atom to which R3 and R4 are attached, wherein the spiro ring may have a nitrogen atom, a carbon atom oxygen, or a sulfur atom, as a ring member atom; the ring formed may be substituted by a halogen atom, a C1 to C6 alkyl group, or an amino group; and the alkyl group may have a group selected from the group consisting of a halogen atom, a C1 to C6 alkyl group, and a C1 to C6 alkoxy group as a substituent, or (b) exo-methylene group bonded through of a double bond, wherein the exomethylene group may have one or two substituents selected from the group consisting of a hydroxyl group, an amino group, a halogen atom, a C1 to C6 alkylthio group, and a C1 to C6 group alkoxy; "A" represents a nitrogen atom or a partial structure represented by the following formula: (wherein X2 represents a hydrogen atom, a hydroxyl group, a cyano group, a halogen atom, a C1 to C6 alkyl group, a C1 to C6 alkoxy group, a halogenomethyl group, or a halogenomethoxy group, wherein X2 and R1 may be integrated with a sketch portion to form a ring, and the ring formed may have a C1 to C6 group of alkyl as a substituent); W represents -CHR5-, -O-, or -NR6- (wherein R5 represents a hydrogen atom, a halogen atom, a C1 to C6 alkyl group, a C3 to C6 cycloalkyl group, a C2a C6 group of alkenyl, a C2 to C6 alkynyl group, or a C1 to C6 alkoxy group, the cycloalkyl group may have an amino group as a substituent, the alkyl group may have one or more substituents selected from the group consisting of a group hydroxyl, an amino group, a halogen atom, a C1 to C6 alkylthio group, and a C1 to C6 alkoxy group: R5 and R3 or R4 may together form a C3 to C6 cycloalkane or a 5 to 6 heterocycle. 7 members saturated with a carbon atom to which these R s are attached, and the formed cycloalkane or saturated heterocycle may have a C1 to C6 alkyl group or an amino group as a substituent, and R6 represents a hydrogen atom, a group (C1 to C6 alkyl, or a C3 to C6 cycloalkyl group); X1 represents a hydrogen atom or a halogen atom; Y represents a hydrogen atom, or an amino group, a C1 to C6 alkyl group, a C1 to C6 alkylamino group, a C3 to C6 cycloalkyl group, or a group which can be easily transformed by chemical means to an amino group or a C1 to C6 alkylamino group, these groups each being attached to any saturated heterocyclic ring carbon atom; and n is 0 to 2, a salt thereof, or a hydrate of the compound or salt, characterized in that the method comprises admitting to cause a reaction in a mixture containing a compound represented by the formula (2): (where X represents a halogen atom, and R11 R2, X1, and Having the same meanings as defined above), a salt of a compound represented by formula (3): (wherein W, Y, R31 R41 and n have the same meanings as defined above, and a boron derivative in a solvent in the presence of a base to thereby form a boron chelate compound, and to remove a boron chelate portion of the boron chelate compound. Production method according to claim 1, characterized in that the boron derivative is composed of trifluoroboro. Production method according to claim 1 or 2, characterized in that the trifluoroboro compound is a trifluoroboro diethyl ether complex or a trifluoroboro tetrahydrofuran complex. Production method according to any one of claims 1 to 3, characterized in that the mixture is allowed to cause a reaction therein in the presence of a tertiary salt or amine.